It is the purpose of the research proposed in this grant to study an unusual factor produced by lymphocytes, which inhibits malignant cell proliferation in tissue culture. We have called this material "Proliferation Inhibitory Factor" of "PIF". We have recently observed the production of this material when lymphocytes are stimulated by phytohemagglutinin. We anticipate a series of studies in three basic areas: 1) the production of PIF; 2) the characterization of PIF; and 3) studies in the mechanism of action of the PIF. We shall produce the PIF by lymphoid cells from various sources, with a variety of antigenic and mitogenic stimuli. We shall determine optimum time for production and concentration of stimulus. We hope to determine that the production of PIF is an essential part of the delayed hypersensitivity response. We shall assay the PIF by utilizing a number of eukaryocytic and bacterial cells. We shall examine the effect of PIF on diploid and heteroploid cells in regulated and unregulated growth. We shall attempt to determine if the inhibition of growth is related to cell damage or to a general class of humoral regulators of cell growth. We anticipate that PIF will be a unique substance produced by lymphocytes and that it is an essential part of the body's normal defense mechanism involved in the control of the neoplastic cell proliferation. BIBLIOGRAPHIC REFERENCES: Whitcomb, M.E., Merluzzi, V.J. and Cooperband, S.R. The effect of levamisole on human lymphocyte mediator production in vitro. Cell. Immunol. 21: 272-277, 1976. Merluzzi, V.J., Badger, A.M., Kaiser, C.W. and Cooperband, S.R. In vitro stimulation of murine lymphoid cell cultures by levamisole. Clin. Exp. Immunol. 22: 486-492, 1975.